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Peer-reviewedCC BY-NC-NDNature communications

Orthosteric and allosteric inhibition of the brain V-ATPase outside the alternating-access cycle.

  • Eleftherios Kosmidis1,2
  • Maria Fokaeos1,2
  • Christopher G Shuttle1,2
  • Michael Isselstein1,3
  • Alessandra Narducci1
  • Aleksander Cvjetkovic1,4
  • Peter J Johnson5
  • Jesper L Pedersen6
  • Reinhard Jahn7
  • Julia Preobraschenski8,9,10,11
  • Dimitrios Stamou12,13
13 affiliations
  1. 1Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.
  2. 2Illum Biotech, Copenhagen, Denmark.
  3. 3Cancelight, Munich, Germany.
  4. 4Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  5. 5Department of Mathematics, University of Manchester, Manchester, United Kingdom.
  6. 6Department of Mathematics, University of Copenhagen, Copenhagen, Denmark.
  7. 7Laboratory of Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  8. 8Center of Membrane Biochemistry and Lipid Research, Dresden University of Technology, Dresden, Germany.
  9. 9Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.
  10. 10Collaborative Research Center 1690(CRC1690), University of Göttingen, Göttingen, Germany.
  11. 11Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), Georg-August-University Göttingen, Göttingen, Germany.
  12. 12Department of Chemistry, University of Copenhagen, Copenhagen, Denmark. [email protected].
  13. 13Illum Biotech, Copenhagen, Denmark. [email protected].
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Abstract

Active transporters move solutes uphill by harnessing the free energy stored in ATP or ion-motive gradients. A central tenet of molecular pharmacology is that orthosteric and allosteric inhibitors of active transporters act by slowing the transport cycle. We test this foundational premise, previously supported by ensemble-average data, at the single-molecule level. Using endogenous mammalian-brain V-ATPase, we show that bulk acidification can be abolished without any reduction in the single-molecule proton-transport rate. Instead, inhibitors predominantly promote reversible excursions outside the canonical transport cycle into ultralong-lived inactive modes. Overall, our findings establish the existence of two orthogonal axes of pharmacological control (on-cycle catalytic rates and off-cycle mode occupancy) that can be selectively or jointly actuated for precision drug design and likely generalize to other active transporters.

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Cite

BibTeXRIS
BibTeX
@article{kosmidis2026orthosteric,
  title = {{Orthosteric and allosteric inhibition of the brain V-ATPase outside the alternating-access cycle.}},
  author = {Eleftherios Kosmidis and Maria Fokaeos and Christopher G Shuttle and Michael Isselstein and Alessandra Narducci and Aleksander Cvjetkovic and Peter J Johnson and Jesper L Pedersen and Reinhard Jahn and Julia Preobraschenski and Dimitrios Stamou},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-78028-4},
  url = {https://europepmc.org/article/MED/42971968},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Orthosteric and allosteric inhibition of the brain V-ATPase outside the alternating-access cycle.
AU  - Eleftherios Kosmidis
AU  - Maria Fokaeos
AU  - Christopher G Shuttle
AU  - Michael Isselstein
AU  - Alessandra Narducci
AU  - Aleksander Cvjetkovic
AU  - Peter J Johnson
AU  - Jesper L Pedersen
AU  - Reinhard Jahn
AU  - Julia Preobraschenski
AU  - Dimitrios Stamou
PY  - 2026
DA  - 2026/09/28
JO  - Nature communications
DO  - 10.1038/s41467-026-78028-4
UR  - https://europepmc.org/article/MED/42971968
AB  - Active transporters move solutes uphill by harnessing the free energy stored in ATP or ion-motive gradients. A central tenet of molecular pharmacology is that orthosteric and allosteric inhibitors of active transporters act by slowing the transport cycle. We test this foundational premise, previously supported by ensemble-average data, at the single-molecule level. Using endogenous mammalian-brain V-ATPase, we show that bulk acidification can be abolished without any reduction in the single-molecule proton-transport rate. Instead, inhibitors predominantly promote reversible excursions outside the canonical transport cycle into ultralong-lived inactive modes. Overall, our findings establish the existence of two orthogonal axes of pharmacological control (on-cycle catalytic rates and off-cycle mode occupancy) that can be selectively or jointly actuated for precision drug design and likely generalize to other active transporters.
SN  - 2041-1723
ER  -